Mechanical ventilation (MV) provides life-sustaining support that is essential for recovery of most patients with acute lung injury (ALl). However, MV may itself cause lung injury (ventilation-associated lung injury, VALI). This may delay or prevent recovery from acute respiratory failure caused by treatable conditions such as sepsis. Project 1 is designed to develop better techniques of MV to reduce VALI and improve clinical outcomes of ALl patients. This project is a key component of this SCCOR application, which represents an integrated approach to identifying molecular mechanisms of VALI and then translating new knowledge into improved clinical care. The focus of this SCCOR project is high frequency oscillatory ventilation (HFOV). This technology recently became available for use in adult ALl patients, but several issues must be addressed before HFOV can be recommended for widespread use. The Project 1 leader, Roy Brower, M.D. has led several clinical trials that have established the current standard for using conventional mechanical ventilation in ALl. Brett Simon, M.D. Ph.D., project co-leader, is an innovative and accomplished biomedical engineer and physiologist who has made several contributions to understanding the physiology of HFOV. Simon has developed sophisticated imaging tools and large animal models for studying effects of clinical interventions on lung mechanics and gas exchange in ALl. The Project 1 investigators will use state-of-the art clinical, imaging, and molecular tools and novel phenotyping instruments to establish the clinical value of HFOV. Experiments in Specific Aim 1 will characterize effects of different mechanical ventilation strategies on known biomarkers of VALI and also identify novel molecular pathways in VALI pathogenesis. Experiments in Specific Aim 2 will characterize the interactions between HFOV settings and specific physiologic characteristics of ALl patients. Knowledge gained from Specific Aims 1 and 2 will provide critical information needed to optimize HFOV and conventional MV approaches. Specific Aim 3 consists of an exploratory clinical trial to compare clinical and physiologic indicators of efficacy and safety in patients who receive either an optimized HFOV or optimized conventional MV approach. Completion of these studies will provide insights regarding pathogenesis of VALI and will guide future mechanistic and clinical studies designed to improve clinical outcomes in ALl patients.